Aminoquinoline compounds

ABSTRACT

This invention relates to treating inflammatory and immune diseases with certain aminoquinoline compounds that bind to CXCR3 receptors. The aminoquinoline compounds are covered by the formula (I) shown below. Each variable is defined in the specification.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] Pursuant to 35 USC § 119(e), this application claims priority to U.S. Provisional Application Serial No. 60/462,495, filed Apr. 11, 2003, and U.S. Provisional Application Serial No. 60/551,750, filed Mar. 9, 2004, the contents of which are incorporated herein by reference.

BACKGROUND

[0002] Chemokines have been classified into four groups according to their structures. CXC and CC chemokines, the two large groups, feature the presence and absence of an amino acid, respectively, between the first two cysteine residues in a conserved four-cysteine motif (Mackay C. R., Nat. Immunol., (2001) 2:95; Olson et al., Am. J. Physiol. Regul. Integr. Comp. Physiol., (2002) 283:R7). CXCR3 is the first chemokine receptor found to be highly induced by T cell activation (Loetscher et al., J. Exp. Med., (1996) 184:963). CXCR3 is expressed on some circulating blood T cells, B cells, and natural killer cells (Qin et al., J. Clin. Invest., (1998) 101:746). For example, expression of CXCR3 is induced virtually by all T cells in synovial fluid of rheumatoid arthritis and in various inflamed tissues (e.g., ulcerative colitis, chronic vaginitis, and sarcoidosis), particularly in perivascular regions. However, few T cells in normal lymph nodes are induced to express CXCR3 (Agostini et al., J. Immunol., (1998) 161:6413). Expression and responsiveness of CXCR3 can be markedly increased by T cell activation (Rabin et al., J. Immunol., (1999) 162:3840). CXCR3 is also consistently detected in functional forms on transformed B cells obtained from chronic lymphocytic leukemia patients (Trentin et al., J. Clin. Invest., (1999) 104:115).

[0003] CXCR3 binds to three highly potent, inflammation-inducible, ELR-negative CXC chemokines, i.e., I-TAC, Mig, and IP-10. These three chemokines chemoattract and induce calcium influx in activated T cells, tumor-infiltrating lymphocytes, and CXCR3-transfected cells (Loetscher et al., Eur. J. Immunol., (1998) 28:3696; Cole et al., J. Exp. Med., (1998) 187:2009; Weng et al., J. Biol. Chem., (1998) 273:18288). CXCR3 signaling appears to be an important mechanism for selective homing of activated/effector cells, which are known to accumulate preferentially at inflammatory sites and in many tumors. For example, IP-10 is expressed abundantly at various inflammatory sites, particularly those characterized by T cell infiltration, such as in tissues affected by delayed type hypersensitivity responses, experimental autoimmune encephalomyelitis, or a transplant undergoing rejection (Qin et al., J. Clin. Invest., (1998) 101:746). CXCR3 ligand-induced recruitment of leukocytes is thought to be an essential step in the pathogenesis of tissue-specific autoimmune inflammatory diseases, as well as in graft rejection (Hancock et al., J. Exp. Med., (2000) 192:1515).

SUMMARY

[0004] This invention is based on the discovery that certain aminoquinoline compounds are effective in treating inflammatory and immune diseases through their binding to CXCR3 receptors.

[0005] In one aspect, this invention features aminoquinoline compounds of formula (I) or their salts:

[0006] In this formula, each

is a single bond or a double bond; provided that if one

is a double bond, its neighboring

is not a double bond; each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═, —CR_(a)—, —N═, —N—, —S—, —O—, or a single bond; at most one of

X₁—,

X₂—,

X₃—, and

X₄— being a single bond, and at most two of

X₁—,

X₂—,

X₃—, and

X₄— being —N═, —N—, —S—, or —O—; each of R₁ and R₂, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(b)R_(b)′, —C(O)—OR_(b), —OC(O)—R_(b), —C(O)—R_(b), or halogen; or R₁ and R₂ together are C₅-C₈ heterocycloalkyl; each of R₃ and R₄, independently, is H or -A-N(B)-D; and each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, NO₂, CN, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(c)R_(c)′, —C(O)—OR_(c), —OC(O)—R_(c), —C(O)—R_(c), halogen, or deleted; or R₅ and R₆ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₆ and R₇ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₇ and R₈ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₅ is deleted,

X₁— is —N═, —S—, —O—, or a single bond; if R₆ is deleted,

X₂— is —N═, —S—, —O—, or a single bond; if R₇ is deleted,

X₃— is —N═, —S—, —O—, or a single bond; and if R₈ is deleted,

X₄— is —N═, —S—, —O—, or a single bond. A is C₁-C₁₂ alkyl optionally containing 1-6 heteroatoms, C₂-C₁₂ alkenyl optionally containing 1-6 heteroatoms, C₂-C₁₂ alkynyl optionally containing 1-6 heteroatoms, aryl, heteroaryl, C₁-C₁₀ alkylsulfonyl, arylsulfonyl, C₁-C₁₀ alkylcarbonyl containing 1-6 heteroatoms, C₂-C₂₀ alkylaryl optionally containing 1-6 heteroatoms, C₂-C₂₀ arylalkyl optionally containing 1-6 heteroatoms, C₂-C₂₀ alkylheteroaryl containing 1-6 heteroatoms, or C₂-C₂₀ heteroarylalkyl containing 1-6 heteroatoms. B is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl; or B and A together are heteroaryl. D is H, aryl, heteroaryl, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, —C(O)—R_(d), —SO₂—R_(d), —C(S)—R_(d), —C(O)—NR_(d)R_(d)′, —C(O)—OR_(d), —OC(O)—R_(d), —C(O)—SR_(d), or —SC(O)—R_(d); or D and A together are heteroaryl. Each of R_(a), R_(b), R_(b)′, R_(c), R_(c)′, R_(d), and R_(d)′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl; or R_(d) and R_(d)′ together being C₅-C₇ heterocycloalkyl.

[0007] Referring to formula (I), a subset of the compounds described above are those in which D is of formula (II):

[0008] In formula (II), each

is a single bond or a double bond; provided that if one

is a double bond, its neighboring

is not a double bond; each of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, independently, is —C═, —CR_(e)—, —N═, —N—, —S—, —O—, or a single bond; at most one of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, being a single bond, and at most two of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, being —N═, —N—, —S—, or —O—; each of R₁′ and R₂′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(f)R_(f)′, —C(O)—OR_(f), —OC(O)—R_(f), —C(O)—R_(f), or halogen; or R₁′ and R₂′ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, NO₂, CN, C₁-C₆ alkylamino, C₁-C₁₂dialkylamino, arylamino, diarylamino, —C(O)—NR_(g)R_(g)′, —C(O)—OR_(g), —OC(O)—R_(g), —C(O)—R_(g), halogen, or deleted; or R₃′ and R₄′ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₄′ and R₅′ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₅′ and R₆′ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₃′ is deleted,

X₁′— is —N═, —S—, —O—, or a single bond; if R₄′ is deleted,

X₂′— is —N═, —S—, —O—, or a single bond; if R₅′ is deleted,

X₃′— is —N═, —S—, —O—, or a single bond; and if R₆′ is deleted,

X₄′— is —N═, —S—, —O—, or a single bond. Each of R_(e), R_(f), R_(f)′, R_(g), and R_(g)′, independently, being H, C₁-C₃ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl. Referring to formula (I), another subset of the compounds described above are those in which A is C₁-C₁₂ alkyl; C₁-C₁₂ alkyl containing 1-6 heteroatoms and optionally substituted with sulfonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl; C₂-C₂₀ alkylaryl optionally containing 1-6 heteroatoms; or aryl; or A and B together are heteroaryl.

[0009] The term “alkyl” refers to a saturated, linear or branched hydrocarbon moiety, such as —CH₃, —CH₂—, or branched —C₃H₇. The term “alkenyl” refers to a linear or branched, non-aromatic hydrocarbon moiety having at least one double bond, such as —CH═CH₂ or —CH═CH—. The term “alkynyl” refers to a linear or branched, non-aromatic hydrocarbon moiety having at least one triple bond, such as —C≡CH or —C≡C—. The term “cycloalkyl” refers to a saturated cyclic hydrocarbon moiety, such as cyclohexyl. The term “cycloalkenyl” refers to a non-aromatic cyclic hydrocarbon moiety having at least one double bond in the ring, such as 2-cyclopentenyl. The term “heterocycloalkyl” refers to a saturated non-aromatic cyclic moiety having at least one ring heteroatom (e.g., O, N, and S), such as 4-tetrahydropyranyl. The term “heterocycloalkenyl” refers to a non-aromatic cyclic moiety having at least one ring heteroatom and at least one double bond in the ring, such as 3,4-dihydropyran-4-yl. The term “alkoxy” refers to a linear or branched, saturated or unsaturated, non-aromatic hydrocarbon moiety containing an oxygen radical, such as —OCH₃ or —OCH═C₂H₅. The term “aryloxy” refers to a moiety having at least one aromatic ring and an oxygen radical bonded to the aromatic ring, such as phenoxy. The term “heteroaryloxy” refers to a moiety having at least one aromatic ring that contains at least one ring heteroatom and an oxygen radical bonded to the aromatic ring, such as 4-pyrindinoxy. The term “aryl” refers to a hydrocarbon moiety having one or more aromatic rings. Examples of an aryl moiety include phenyl, phenylene, naphthyl, naphthylene, pyrenyl, anthryl, and phenanthryl. The term “heteroaryl” refers to a moiety having one or more aromatic rings that contain at least one heteroatom. Examples of a heteroaryl moiety include furyl, furylene, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl and indolyl. The term “alkylaryl” refers to an aryl moiety substituted with unsubstituted or substituted alkyl, such as

[0010] The term “alkylheteroaryl” refers to a heteroaryl moiety substituted with unsubstituted or substituted alkyl. The terms “arylalkyl” and “heteroarylalkyl” respectively refer to an alkyl moiety substituted with unsubstituted or substituted aryl and an alkyl moiety substituted with unsubstituted or substituted heteroaryl, such as benzyl or pyridinylmethyl. Alkylaryl and arylalkyl may optionally contain 1-6 heteroatoms. Alkylheteroaryl and heteroarylalkyl contain 1-6 heteroatoms.

[0011] Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkoxy, aryloxy, heteroaryloxy, aryl, and heteroaryl mentioned herein include both substituted and unsubstituted moieties. Examples of substituents for cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryloxy, heteroaryloxy, aryl, and heteroaryl include C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₁-C₁₀ alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, C₁-C₁₀ alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, amino, C₁-C₁₀ alkylaamino, C₁-C₂₀ dialkylamino, arylamino, diarylamino, C₁-C₁₀ alkylimino, arylimino, amido, carbamoyl, thioamido, thiocarbamoyl, hydroxyl, halogen, thio, C₁-C₁₀ alkylthio, arylthio, cyano, nitro, acyl, acyloxy, carboxyl, and carboxylic ester. Examples of substituents for alkyl, alkenyl, alkynyl, and alkoxy include all of the above substitutents except C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, and C₂-C₁₀ alkynyl. Cycloalkyl, cycloalkenyl, heterocycloalkyl heterocycloalkenyl, aryl, and heteroaryl also include fused groups.

[0012] In another aspect, this invention features aminoquinoline compounds of formula (I) shown above except that each of R₁ and R₂, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(b)R_(b)′, —OC(O)—R_(b), —C(O)—R_(b), or halogen; or R₁ and R₂ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, NO₂, CN, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(c)R_(c)′, —C(O)—OR_(c), —OC(O)—R_(c), —C(O)—R_(c), or deleted; or R₅ and R₆ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₆ and R₇ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₇ and R₈ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₅ is deleted,

X₁— is —N═, —S—, —O—, or a single bond; if R₆ is deleted,

X₂— is —N═, —S—, —O—, or a single bond; if R₇ is deleted,

X₃— is —N═, —S—, —O—, or a single bond; and if R₈ is deleted,

X₄— is —N═, —S—, —O—, or a single bond; and further provided that not all of R₅, R_(6,) R₇, and R₈ are H;

[0013] In still another aspect, this invention features a method for treating an inflammatory or immune disease. The method includes administering to a subject in need of treatment of an effective amount of one or more compounds of formula (I) shown above except that each of R₁ and R₂, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(b)R_(b)′, —C(O)—OR_(b), —OC(O)—R_(b), —C(O)—R_(b), or halogen; or R₁ and R₂ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, NO₂, CN, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(c)R_(c)′, —C(O)—OR_(c), —OC(O)—R_(c), —C(O)—R_(c), halogen, or deleted; or R₅ and R₆ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₆ and R₇ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₇ and R₈ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₅ is deleted,

X₁— is —N═, —S—, —O—, or a single bond; if R₆ is deleted,

X₂— is —N═, —S—, —O—, or a single bond; if R₇ is deleted,

X₃— is —N═, —S—, —O—, or a single bond; and if R₈ is deleted,

X₄— is —N═, —S—, —O—, or a single bond; in which B is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl; or B and A together are C₅-C₇ heterocycloalkyl or heteroaryl; and D is H, aryl, heteroaryl, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, —C(O)—R_(d), —SO₂—R_(d), —C(S)—R_(d), —C(O)—NR_(d)R_(d)′, —C(O)—OR_(d), —OC(O)—R_(d), —C(O)—SR_(d), or —SC(O)—R_(d); or D and A together are C₅-C₇ heterocycloalkyl or heteroaryl.

[0014] “Treatment” refers to administering one or more aminoquinoline compounds to a subject, who has an inflammatory or immune disease, a symptom of such a disease, or a predisposition toward such a disease, with the purpose to confer a therapeutic effect, e.g., to cure, relieve, alter, affect, ameliorate, or prevent the inflammatory or immune disease, the symptom of it, or the predisposition toward it. “An effective amount” refers to the amount of one or more active aminoquinoline compounds that is required to confer a therapeutic effect on a treated subject.

[0015] An inflammatory disease is characterized by a local or systemic, acute or chronic inflammation. An immune disease is characterized by a hyper- or hypo-reaction of the immune system. Examples of inflammatory or immune diseases include multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, atherosclerosis, encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, psoriasis, eczema, uticaria, Type I diabetes, asthma, conjunctivitis, otitis, allergic rhinitis, chronic obstructive pulmonary disease, sinusitis, dermatitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, Behcet's syndrome, gout, cancer, viral infections, bacterial infections, organ transplant conditions, skin transplant conditions, graft rejection (including allograft rejection and graft-versus-host disease), spondyloarthropathies, scleroderma, vasculitis, and psoriasis (including T-cell mediated psoriasis).

[0016] A subject in need of treatment of an inflammatory or immune disease can also be concurrently administered with an aminoquinoline compound described above and one or more other therapeutic agents at the same time or at different times during the period of treatment. Examples of such a therapeutic agent include a steroidal or a non-steroidal anti-inflammatory drug, a COX2 inhibitor, a leukotriene receptor inhibitor, a prostaglandin modulator, a TNF modulator, and an immunosuppressive agent (e.g., cyclosporine A).

[0017] In a further aspect, this invention features a pharmaceutical composition that contains an effective amount of at least one of the above-mentioned aminoquinoline compounds and a pharmaceutically acceptable carrier.

[0018] The aminoquinoline compounds described above include the compounds themselves, as well as their salts and their prodrugs, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on an aminoquinoline compound. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, maleate, succinate, fumarate, tartrate, salicylate, lactate, naphthalenesulfonate, and acetate. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on an aminoquinoline compound. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. The aminoquinoline compounds also include those salts containing quaternary nitrogen atoms. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing active aminoquinoline compounds.

[0019] Also within the scope of this invention is a composition containing one or more of the aminoquinoline compounds described above for use in treating an inflammatory disease or an immune disease, and the use of such a composition for the manufacture of a medicament for the just-mentioned treatment.

[0020] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

DETAILED DESCRIPTION

[0021] Shown below are exemplary compounds, compounds 1-190, of this invention.

[0022] The scheme below depicts the syntheses of exemplary aminoquinoline compounds, i.e., compounds 1-190. Details of preparation of these compounds are provided in Examples 1-190, respectively.

[0023] For example, referring to the scheme shown above, an aniline derivative is reacted with a β-keto ester to produce an enamine. A quinolinone derivative is formed through a ring closure reaction by heating the enamine at a high temperature for a short period time, and is then converted to a 4-chloro-quinoline derivative upon reacting with phosphorus oxychloride. A compound described in the summary section above can be obtained by (1) reacting the 4-chloro-quinoline derivative with a linker containing at least two amino groups in a 2/1 ratio (Route I), (2) reacting the 4-chloro-quinoline derivative with a linker in a 1/1 ratio and then with another chloro-containing compound in a 1/1 ratio (Routes n and III), or (3) reacting the 4-chloro-quinoline derivative with an amino-containing compound (Route IV).

[0024] Other amionquinoline compounds can be prepared using other suitable starting materials following the synthetic routes disclosed herein and other synthetic methods known in the art. The methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the aminoquinoline compounds. In addition, various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable aminoquinoline compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.

[0025] The aminoquinoline compounds mentioned herein may contain a non-aromatic double bond and one or more asymmetric centers. Thus, they can occur as racemates and racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans-isomeric forms. All such isomeric forms are contemplated.

[0026] Also within the scope of this invention is a pharmaceutical composition contains an effective amount of at least one aminoquinoline compound described above and a pharmaceutical acceptable carrier. Further, this invention covers a method of administering an effective amount of one or more of the aminoquinoline compounds to a patient with an inflammatory or immune disease. Effective doses will vary, as recognized by those skilled in the art, depending on the types of diseases treated, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatment.

[0027] To practice the method of the present invention, a composition having one or more aminoquinoline compounds can be administered parenterally, orally, nasally, rectally, topically, or buccally. The term “parenteral” as used herein refers to subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection, as well as any suitable infusion technique.

[0028] A sterile injectable composition can be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides). Fatty acid, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long chain alcohol diluent or dispersant, carboxymethyl cellulose, or similar dispersing agents. Other commonly used surfactants such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purpose of formulation.

[0029] A composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions. In the case of tablets, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.

[0030] A nasal aerosol or inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation. For example, such a composition can be prepared as a solution in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. A composition having one or more active aminoquinoline compounds can also be administered in the form of suppositories for rectal administration.

[0031] The carrier in the pharmaceutical composition must be “acceptable” in the sense that it is compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject to be treated. One or more solubilizing agents can be utilized as pharmaceutical excipients for delivery of an active aminoquinoline compound. Examples of other carriers include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.

[0032] The aminoquinoline compounds of this invention can be preliminarily screened for their efficacy in treating inflammatory or immune diseases by an in vitro assay (See Example 191 below) and then confirmed by animal experiments and clinical trials. Other methods will also be apparent to those of ordinary skill in the art.

[0033] The specific examples below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All publications cited herein are hereby incorporated by reference in their entirety.

EXAMPLE 1

[0034] Compound 1 was prepared following the procedures described below:

[0035] p-Toluenesulfonic acid (catalytic amount) was added to a solution of p-methylaniline (10.7 g, 100 mmol) and ethyl acetoacetate (13.0 g, 110 mmol) in benzene (250 mL) at room temperature. The reaction mixture was refluxed with a Dean-Stark apparatus over night. After cooling down to room temperature, the reaction mixture was concentrated and purified by column chromatography (5% ethyl acetate in n-hexane) to give 3-p-tolylamino-but-2-enoic acid ethyl ester (18.6 g, 85% yield).

[0036] 3-p-Tolylamino-but-2-enoic acid ethyl ester (21.9 g, 100 mmol) thus obtained was dissolved in phenyl ether (17.0 g, 100 mmol). The solution was heated to 120° C. for 5 minutes. The temperature of reaction mixture was then quickly raised up to 250° C. for 15 min under nitrogen. After cooling down to room temperature, the reaction mixture was purified by re-crystallization from ethyl acetate (30 mL) to give 2,6-dimethyl-1H-quinolin-4-one (13.8 g, 80% yield).

[0037] A mixture of 2,6-dimethyl-1H-quinolin-4-one (17.3 g, 100 mmol) and phosphorus oxychloride (30 mL) was heated at 80° C. for 3 h. After cooling down to room temperature, the reaction mixture was poured onto ice. The resulting solution was carefully alkalinized to pH 8-9 with 0.5 N NaOH and saturated Na₂CO₃. The solution was extracted with CH₂Cl₂ (200 mL×3). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (10% ethyl acetate in n-hexane) to give 4-chloro-2,6-dimethyl-quinoline (12.4 g, 65% yield).

[0038] 4-Chloro-2,6-dimethyl-quinoline (211 mg, 1.1 mmol) and 1,4-butadiamine (44 mg, 0.5 mmol) were dissolved in pentanol (5 mL). The solution was kept under reflux over night. After cooling down to room temperature, 0.5 N NaOH (5 mL) was added to the above reaction mixture. The reaction mixture was stirred at room temperature for another 30 minutes and then extracted with CH₂Cl₂ (10 mL×3). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was then purified by column chromatography (2% Et₃N in 1:1 n-hexane and ethyl acetate) to give compound 1.

[0039] LC/MS (M+1)⁺: 399.0.

EXAMPLE 2

[0040] Compound 2 was prepared in a manner similar to that described in Example 1.

[0041] LC/MS (M+1)⁺: 427.0.

EXAMPLE 3

[0042] Compound 3 was prepared in a manner similar to that described in Example 1.

[0043] LC/MS (M+1)⁺: 441.0.

EXAMPLE 4

[0044] Compound 4 was prepared in a manner similar to that described in Example 1.

[0045] LC/MS (M+1)⁺: 469.1.

EXAMPLE 5

[0046] Compound 5 was prepared in a manner similar to that described in Example 1.

[0047] LC/MS (M+1)⁺: 413.1.

EXAMPLE 6

[0048] Compound 6 was prepared in a manner similar to that described in Example 1.

[0049] LC/MS (M+1)⁺: 455.0.

EXAMPLE 7

[0050] Compound 7 was prepared in a manner similar to that described in Example 1.

[0051] LC/MS (M+1)⁺: 431.1.

EXAMPLE 8

[0052] Compound 8 was prepared in a manner similar to that described in Example 1.

[0053] LC/MS (M+1)⁺: 459.0.

EXAMPLE 9

[0054] Compound 9 was prepared in a manner similar to that described in Example 1.

[0055] LC/MS (M+1)⁺: 461.2.

EXAMPLE 10

[0056] Compound 10 was prepared in a manner similar to that described in Example 1.

[0057] LC/MS (M+1)⁺: 447.2.

EXAMPLE 11

[0058] Compound 11 was prepared in a manner similar to that described in Example 1.

[0059] LC/MS (M+1)⁺: 611.2.

EXAMPLE 12

[0060] Compound 12 was prepared in a manner similar to that described in Example 1.

[0061] LC/MS (M+1)⁺: 597.2.

EXAMPLE 13

[0062] Compound 13 was prepared in a manner similar to that described in Example 1.

[0063] LC/MS (M+1)⁺: 583.2.

EXAMPLE 14

[0064] Compound 14 was prepared in a manner similar to that described in Example 1.

[0065] LC/MS (M+1)⁺: 569.2.

EXAMPLE 15

[0066] Compound 15 was prepared in a manner similar to that described in Example 1.

[0067] LC/MS (M+1)⁺: 463.1.

EXAMPLE 16

[0068] Compound 16 was prepared in a manner similar to that described in Example 1.

[0069] LC/MS (M+1)⁺: 477.1.

EXAMPLE 17

[0070] Compound 17 was prepared in a manner similar to that described in Example 1.

[0071] LC/MS (M+1)⁺: 491.1.

EXAMPLE 18

[0072] Compound 18 was prepared in a manner similar to that described in Example 1.

[0073] LC/MS (M+1)⁺: 435.1.

EXAMPLE 19

[0074] Compound 19 was prepared in a manner similar to that described in Example 1.

[0075] LC/MS (M+1)⁺: 466.9.

EXAMPLE 20

[0076] Compound 20 was prepared in a manner similar to that described in Example 1.

[0077] LC/MS (M+1)⁺: 556.8.

EXAMPLE 21

[0078] Compound 21 was prepared in a manner similar to that described in Example 1.

[0079] LC/MS (M+1)⁺: 481.2.

EXAMPLE 22

[0080] Compound 22 was prepared in a manner similar to that described in Example 1.

[0081] LC/MS (M+1)⁺: 511.3.

EXAMPLE 23

[0082] Compound 23 was prepared in a manner similar to that described in Example 1.

[0083] LC/MS (M+1)⁺: 736.8.

EXAMPLE 24

[0084] Compound 24 was prepared in a manner similar to that described in Example 1.

[0085] LC/MS (M+1)⁺: 615.0.

EXAMPLE 25

[0086] Compound 25 was prepared in a manner similar to that described in Example 1.

[0087] LC/MS (M+1)⁺: 479.2.

EXAMPLE 26

[0088] Compound 26 was prepared in a manner similar to that described in Example 1.

[0089] LC/MS (M+1)⁺: 493.1.

EXAMPLE 27

[0090] Compound 27 was prepared in a manner similar to that described in Example 1.

[0091] LC/MS (M+1)⁺: 507.3.

EXAMPLE 28

[0092] Compound 28 was prepared in a manner similar to that described in Example 1.

[0093] LC/MS (M+1)⁺: 507.1.

EXAMPLE 29

[0094] Compound 29 was prepared in a manner similar to that described in Example 1.

[0095] LC/MS (M+1)⁺: 599.1.

EXAMPLE 30

[0096] Compound 30 was prepared in a manner similar to that described in Example 1.

[0097] LC/MS (M+1)⁺: 469.0.

EXAMPLE 31

[0098] Compound 31 was prepared in a manner similar to that described in Example 1.

[0099] LC/MS (M+1)⁺: 463.1.

EXAMPLE 32

[0100] Compound 32 was prepared in a manner similar to that described in Example 1.

[0101] LC/MS (M+1)⁺: 384.9.

EXAMPLE 33

[0102] Compound 33 was prepared in a manner similar to that described in Example 1.

[0103] LC/MS (M+1)⁺: 447.2.

EXAMPLE 34

[0104] Compound 34 was prepared in a manner similar to that described in Example 1.

[0105] LC/MS (M+1)⁺: 419.1.

EXAMPLE 35

[0106] Compound 35 was prepared in a manner similar to that described in Example 1.

[0107] LC/MS (M+1)⁺: 469.2.

EXAMPLE 36

[0108] Compound 36 was prepared in a manner similar to that described in Example 1.

[0109] LC/MS (M+1)⁺: 471.2.

EXAMPLE 37

[0110] Compound 37 was prepared in a manner similar to that described in Example 1.

[0111] LC/MS (M+1)⁺: 562.0.

EXAMPLE 38

[0112] Compound 38 was prepared in a manner similar to that described in Example 1.

[0113] LC/MS (M+1)⁺: 523.0.

EXAMPLE 39

[0114] Compound 39 was prepared in a manner similar to that described in Example 1.

[0115] LC/MS (M+1)⁺: 559.2.

EXAMPLE 40

[0116] Compound 40 was prepared in a manner similar to that described in Example 1.

[0117] LC/MS (M+1)⁺: 414.2.

EXAMPLE 41

[0118] Compound 41 was prepared in a manner similar to that described in Example 1.

[0119] LC/MS (M+1)⁺: 584.0.

EXAMPLE 42

[0120] Compound 42 was prepared in a manner similar to that described in Example 1.

[0121] LC/MS (M+1)⁺: 554.0.

EXAMPLE 43

[0122] Compound 43 was prepared in a manner similar to that described in Example 1.

[0123] LC/MS (M+1)⁺: 568.0.

EXAMPLE 44

[0124] Compound 44 was prepared in a manner similar to that described in Example 1.

[0125] LC/MS (M+1)⁺: 633.9.

EXAMPLE 45

[0126] Compound 45 was prepared in a manner similar to that described in Example 1.

[0127] LC/MS (M+1)⁺: 431.2.

EXAMPLE 46

[0128] Compound 46 was prepared in a manner similar to that described in Example 1.

[0129] LC/MS (M+1)⁺: 563.1.

EXAMPLE 47

[0130] Compound 47 was prepared in a manner similar to that described in Example 1.

[0131] LC/MS (M+1)⁺: 652.8.

EXAMPLE 48

[0132] Compound 48 was prepared in a manner similar to that described in Example 1.

[0133] LC/MS (M+1)⁺: 454.0.

EXAMPLE 49

[0134] Compound 57 was prepared in a manner similar to that described in Example 1.

[0135] LC/MS (M+1)⁺: 598.1.

EXAMPLE 50

[0136] Compound 50 was prepared in a manner similar to that described in Example 1.

[0137] LC/MS (M+1)⁺: 611.9.

EXAMPLE 51

[0138] Compound 51 was prepared in a manner similar to that described in Example 1.

[0139] LC/MS (M+1)⁺: 623.9.

EXAMPLE 52

[0140] Compound 52 was prepared in a manner similar to that described in Example 1.

[0141] LC/MS (M+1)⁺: 634.0.

EXAMPLE 53

[0142] Compound 53 was prepared following the procedures described below:

[0143] 4-Chloro-2,6-dimethyl-quinoline (1.9 g, 10 mmol) obtained in Example 1 and 1,6-hexadiamine (2.3 g, 20 mmol) were dissolved in pentanol (40 mL). The solution was kept under reflux over night. After cooling down to room temperature, 0.5 N NaOH (5 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 30 minutes and then extracted with CH₂Cl₂ (10 mL×3). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (2% Et₃N in 1:2 n-hexane and ethyl acetate) to give N1-(2,6-dimethyl-quinolin-4-yl)-hexane-1,5-diamine (1.9 g, 70% yield).

[0144] N1-(2,6-Dimethyl-quinolin-4-yl)-hexane-1,5-diamine (271 mg, 1.0 mmol) thus obtained, 4-chloro-6-methoxy-2-methyl-quinoline (228 mg, 1.1 mmol) (obtained following the procedure described in Example 1), and sodium iodide (catalytic amount) were added in pentanol (10 mL). The reaction mixture was kept under reflux over night. After cooling down to room temperature, 0.5 N NaOH (5 mL) was added to the reaction mixture. The reaction was stirred at room temperature for another 30 minutes and then extracted with CH₂Cl₂ (10 mL×3). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The product was purified by column chromatography (2% Et₃N in 1:1 n-hexane and ethyl acetate) to give compound 53.

[0145] LC/MS (M+1)⁺: 430.2.

EXAMPLE 54

[0146] Compound 54 was prepared in a manner similar to that described in Example 53.

[0147] LC/MS (M+1)⁺: 519.2.

EXAMPLE 55

[0148] Compound 55 was prepared in a manner similar to that described in Example 53.

[0149] LC/MS (M+1)⁺: 427.2.

EXAMPLE 56

[0150] Compound 56 was prepared in a manner similar to that described in Example 53.

[0151] LC/MS (M+1)⁺: 467.2.

EXAMPLE 57

[0152] Compound 57 was prepared in a manner similar to that described in Example 53.

[0153] LC/MS (M+1)⁺: 453.2.

EXAMPLE 58

[0154] Compound 58 was prepared in a manner similar to that described in Example 53.

[0155] LC/MS (M+1)⁺: 467.2.

EXAMPLE 59

[0156] Compound 59 was prepared in a manner similar to that described in Example 53.

[0157] LC/MS (M+1)⁺: 615.0.

EXAMPLE 60

[0158] Compound 60 was prepared in a manner similar to that described in Example 53.

[0159] LC/MS (M+1)⁺: 543.2.

EXAMPLE 61

[0160] Compound 61 was prepared in a manner similar to that described in Example 53.

[0161] LC/MS (M+1)⁺: 537.2.

EXAMPLE 62

[0162] Compound 62 was prepared in a manner similar to that described in Example 53.

[0163] LC/MS (M+1)⁺: 546.2.

EXAMPLE 63

[0164] Compound 63 was prepared in a manner similar to that described in Example 53.

[0165] LC/MS (M+1)⁺: 635.2.

EXAMPLE 64

[0166] Compound 64 was prepared following the procedures described below:

[0167] 4-Chloro-2,6-dimethyl-quinoline (191 mg, 1.0 mmol) obtained in Example 1 and 4-amino-N-thiazol-2-yl-benzenesulfonamide (280 mg, 1.1 mmol) were dissolved in pentanol (5 mL). The solution was kept under reflux over night. After cooling down to room temperature, 0.5 N NaOH (5 mL) was added to the reaction solution. The reaction mixture was stirred at room temperature for another 30 minutes and then extracted with CH₂Cl₂ (10 mL×3). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (2% Et₃N in ratio 1:1 n-hexane and ethyl acetate) to give compound 64 (328 mg, 80% yield).

[0168] LC/MS (M+1)⁺: 410.8.

EXAMPLE 65

[0169] Compound 65 was prepared following the procedures described in the first paragraph of Example 53.

[0170] LC/MS (M+1)⁺: 272.0.

EXAMPLE 66

[0171] Compound 66 was prepared in a manner similar to that described in the first paragraph of Example 53.

[0172] LC/MS (M+1)⁺: 258.2.

EXAMPLE 67

[0173] Compound 67 was prepared in a manner similar to that described in Example 64.

[0174] LC/MS (M+1)⁺: 316.1.

EXAMPLE 68

[0175] Compound 68 was prepared following the procedures described below:

[0176] Pyridine-2-carbaldehyde (210 mg, 1.1 mmol), {2-[2-(2-amino-phenyl)-ethyl]-phenyl}-(2,6-dimethyl-quinolin-4-yl)-amine (367 mg, 1.0 mmol) (This compound was prepared in a manner similar to that described in step 1 of Example 53.), and 10 wt % Pd/C (catalytic amount) were dissolved in MeOH (20 mL). The reaction mixture was kept under pressure (60 psi) with H₂ over night. After releasing the pressure, the reaction mixture was filtered and concentrated. The crude product was purified by column chromatography (2% Et₃N in 1:1 n-hexane and ethyl acetate) to give compound 68 (459 mg, 85% yield).

[0177] LC/MS (M+1)⁺: 459.0.

EXAMPLE 69

[0178] Compound 69 was prepared in a manner similar to that described in the first paragraph of Example 53.

[0179] LC/MS (M+1)⁺: 460.1.

EXAMPLE 70

[0180] Compound 70 was prepared in a manner similar to that described in Example 68.

[0181] LC/MS (M+1)⁺: 551.2.

EXAMPLE 71

[0182] Compound 71 was prepared in a manner similar to that described in the first paragraph of Example 53.

[0183] LC/MS (M+1)⁺: 387.1.

EXAMPLE 72

[0184] Compound 72 was prepared in a manner similar to that described in the first paragraph of Example 53.

[0185] LC/MS (M+1)⁺: 298.2.

EXAMPLE 73

[0186] Compound 73 was prepared in a manner similar to that described in Example 53.

[0187] LC/MS (M+1)⁺: 443.2.

EXAMPLE 74

[0188] Compound 74 was prepared in a manner similar to that described in Example 1.

[0189] LC/MS (M+1)⁺: 651.1.

EXAMPLE 75

[0190] Compound 75 was prepared in a manner similar to that described in Example 1.

[0191] LC/MS (M+1)⁺: 535.1.

EXAMPLE 76

[0192] Compound 76 was prepared in a manner similar to that described in Example 1.

[0193] LC/MS (M+1)⁺: 479.3.

EXAMPLE 77

[0194] Compound 77 was prepared in a manner similar to that described in Example 1.

[0195] LC/MS (M+1)⁺: 563.4.

EXAMPLE 78

[0196] Compound 78 was prepared in a manner similar to that described in Example 1.

[0197] LC/MS (M+1)⁺: 495.3.

EXAMPLE 79

[0198] Compound 79 was prepared in a manner similar to that described in Example 1.

[0199] LC/MS (M+1)⁺: 572.2.

EXAMPLE 80

[0200] Compound 80 was prepared in a manner similar to that described in Example 1.

[0201] LC/MS (M+1)⁺: 598.3.

EXAMPLE 81

[0202] Compound 81 was prepared in a manner similar to that described in Example 1.

[0203] LC/MS (M+1)⁺: 638.1.

EXAMPLE 82

[0204] Compound 82 was prepared in a manner similar to that described in Example 1.

[0205] LC/MS (M+1)⁺: 756.1.

EXAMPLE 83

[0206] Compound 83 was prepared in a manner similar to that described in Example 1.

[0207] LC/MS (M+1)⁺: 630.2.

EXAMPLE 84

[0208] Compound 84 was prepared in a manner similar to that described in Example 1.

[0209] LC/MS (M+1)⁺: 634.2.

EXAMPLE 85

[0210] Compound 85 was prepared in a manner similar to that described in Example 1.

[0211] LC/MS (M+1)⁺: 546.1.

EXAMPLE 86

[0212] Compound 86 was prepared in a manner similar to that described in Example 1.

[0213] LC/MS (M+1)⁺: 614.1.

EXAMPLE 87

[0214] Compound 87 was prepared in a manner similar to that described in Example 1.

[0215] LC/MS (M+1)⁺: 612.2.

EXAMPLE 88

[0216] Compound 88 was prepared in a manner similar to that described in Example 1.

[0217] LC/MS (M+1)⁺: 652.1.

EXAMPLE 89

[0218] Compound 89 was prepared in a manner similar to that described in Example 1.

[0219] LC/MS (M+1)⁺: 692.3.

EXAMPLE 90

[0220] Compound 90 was prepared in a manner similar to that described in Example 1.

[0221] LC/MS (M+1)⁺: 702.0.

EXAMPLE 91

[0222] Compound 91 was prepared in a manner similar to that described in Example 1.

[0223] LC/MS (M+1)⁺: 616.2.

EXAMPLE 92

[0224] Compound 92 was prepared in a manner similar to that described in Example 1.

[0225] LC/MS (M+1)⁺: 560.2.

EXAMPLE 93

[0226] Compound 93 was prepared in a manner similar to that described in Example 1.

[0227] LC/MS (M+1)⁺: 600.3.

EXAMPLE 94

[0228] Compound 94 was prepared in a manner similar to that described in Example 1.

[0229] LC/MS (M+1)⁺: 588.2.

EXAMPLE 95

[0230] Compound 95 was prepared in a manner similar to that described in Example 1.

[0231] LC/MS (M+1)⁺: 666.2.

EXAMPLE 96

[0232] Compound 96 was prepared in a manner similar to that described in Example 1.

[0233] LC/MS (M+1)⁺: 574.2.

EXAMPLE 97

[0234] Compound 97 was prepared in a manner similar to that described in the first paragraph of Example 53, the intermediate thus obtained was then treated with biphenylacetyl chloride and worked up following the procedures described in Example 68.

[0235] LC/MS (M+1)⁺: 528.1.

EXAMPLE 98

[0236] Compound 98 was prepared in a manner similar to that described in Example 53.

[0237] LC/MS (M+1)⁺: 502.1.

EXAMPLE 99

[0238] Compound 99 was prepared in a manner similar to that described in Example 53.

[0239] LC/MS (M+1)⁺: 508.5.

EXAMPLE 100

[0240] Compound 100 was prepared in a manner similar to that described in Example 53.

[0241] LC/MS (M+1)⁺: 629.3.

EXAMPLE 101

[0242] Compound 101 was prepared in a manner similar to that described in Example 53.

[0243] LC/MS (M+1)⁺: 636.2.

EXAMPLE 102

[0244] Compound 102 was prepared in a manner similar to that described in Example 53.

[0245] LC/MS (M+1)⁺: 674.1.

EXAMPLE 103

[0246] Compound 103 was prepared in a manner similar to that described in Example 53.

[0247] LC/MS (M+1)⁺: 622.2.

EXAMPLE 104

[0248] Compound 104 was prepared in a manner similar to that described in Example 53.

[0249] LC/MS (M+1)⁺: 636.2.

EXAMPLE 105

[0250] Compound 105 was prepared in a manner similar to that described in Example 53.

[0251] LC/MS (M+1)⁺: 650.2.

EXAMPLE 106

[0252] Compound 106 was prepared in a manner similar to that described in Example 53.

[0253] LC/MS (M+1)⁺: 688.1.

EXAMPLE 107

[0254] Compound 107 was prepared in a manner similar to that described in Example 53.

[0255] LC/MS (M+1)⁺: 692.2.

EXAMPLE 108

[0256] Compound 108 was prepared in a manner similar to that described in Example 53.

[0257] LC/MS (M+1)⁺: 686.2.

EXAMPLE 109

[0258] Compound 109 was prepared in a manner similar to that described in Example 53.

[0259] LC/MS (M+1)⁺: 580.2.

EXAMPLE 110

[0260] Compound 110 was prepared following the procedures described below:

[0261] Compound 26 (160 mg) and methyl iodide (460 mg) were added in 3 mL of THF and the mixture was refluxed for 3 hours. The precipitate thus obtained was collected by filtration, washed with ether, and dried to give the desired product.

[0262] LC/MS (M−1)⁺: 520.2.

EXAMPLE 111

[0263] Compound 111 was prepared in a manner similar to that described in Example 110.

[0264] LC/MS (M−1)⁺: 455.7.

EXAMPLE 112

[0265] Compound 112 was prepared in a manner similar to that described in Example 110.

[0266] LC/MS (M−1)⁺: 550.2.

EXAMPLE 113

[0267] Compound 113 was prepared in a manner similar to that described in Example 110.

[0268] LC/MS (M−1)⁺: 579.3.

EXAMPLE 114

[0269] Compound 114 was prepared in a manner similar to that described in Example 110.

[0270] LC/MS (M−1)⁺: 523.3.

EXAMPLE 115

[0271] Compound 115 was prepared in a manner similar to that described in Example 110.

[0272] LC/MS (M−1)⁺: 662.2.

EXAMPLE 116

[0273] Compound 116 was prepared in a manner similar to that described in Example 110.

[0274] LC/MS (M−1)⁺: 666.2.

EXAMPLE 117

[0275] Compound 117 was prepared in a manner similar to that described in Example 110.

[0276] LC/MS (M−1)⁺: 640.3.

EXAMPLE 118

[0277] Compound 118 was prepared in a manner similar to that described in Example 110.

[0278] LC/MS (M−1)⁺: 680.2.

EXAMPLE 119

[0279] Compound 119 was prepared in a manner similar to that described in Example 110.

[0280] LC/MS (M−1)⁺: 720.4.

EXAMPLE 120

[0281] Compound 120 was prepared in a manner similar to that described in Example 110.

[0282] LC/MS (M−1)⁺: 588.2.

EXAMPLE 121

[0283] Compound 121 was prepared in a manner similar to that described in Example 110.

[0284] LC/MS (M−1)⁺: 644.3.

EXAMPLE 122

[0285] Compound 122 was prepared in a manner similar to that described in Example 110.

[0286] LC/MS (M−1)⁺: 616.2.

EXAMPLE 123

[0287] Compound 123 was prepared following the procedures described below:

[0288] Compound 54 (160 mg) was added in 5 mL of 2-iodoethanol and the solution was refluxed for 3 hours. The precipitate thus formed was collected by filtration, washed with ether, and dried to give the desired product.

[0289] LC/MS (M−1)⁺: 607.8.

EXAMPLE 124

[0290] Compound 124 was prepared in a manner similar to that described in Example 123.

[0291] LC/MS (M−1)⁺: 547.8.

EXAMPLE 125

[0292] Compound 125 was prepared in a manner similar to that described in Example 123.

[0293] LC/MS (M−1)⁺: 664.2.

EXAMPLE 126

[0294] Compound 126 was prepared in a manner similar to that described in Example 123.

[0295] LC/MS (M−1)⁺: 678.2.

EXAMPLE 127

[0296] Compound 127 was prepared in a manner similar to that described in Example 123.

[0297] LC/MS (M−1)⁺: 702.1.

EXAMPLE 128

[0298] Compound 128 was prepared in a manner similar to that described in Example 123.

[0299] LC/MS (M−1)⁺: 720.2.

EXAMPLE 129

[0300] Compound 129 was prepared in a manner similar to that described in Example 123.

[0301] LC/MS (M−1)⁺: 714.3.

EXAMPLE 130

[0302] Compound 130 was prepared following the procedures described below:

[0303] Methyl iodide (3 mL) and 4,6-dichloro-2-methylquinoline (2 g) were heated in CH₃CN at 65° C. for 40 hours. The precipitate thus formed was collected by filtration, washed with ether, and dried by nitrogen flow and by vacuum to give a quaternary quinolinium salt (2.1 g).

[0304] Compound 81 (92.8 mg) and quinolinium salt (70.9 mg) obtained above were added in 3 mL of CH₃CN. The mixture was refluxed for 12 hours. The precipitation thus obtained was collected by filtration, washed with ether, and dried to give the desired product.

[0305] LC/MS (M)⁺: 652.2.

EXAMPLE 131

[0306] Compound 131 was prepared in a manner similar to that described in Example 130.

[0307] LC/MS (M)⁺: 515.

EXAMPLE 132

[0308] Compound 132 was prepared in a manner similar to that described in Example 130.

[0309] LC/MS (M)⁺: 481.2.

EXAMPLE 133

[0310] Compound 133 was prepared in a manner similar to that described in Example 130.

[0311] LC/MS (M)⁺: 521.2.

EXAMPLE 134

[0312] Compound 134 was prepared in a manner similar to that described in Example 130.

[0313] LC/MS (M)⁺: 521.2.

EXAMPLE 135

[0314] Compound 135 was prepared in a manner similar to that described in Example 1.

[0315] LC/MS (M+1)⁺: 643.

EXAMPLE 136

[0316] Compound 136 was prepared in a manner similar to that described in Example 1.

[0317] LC/MS (M+1)⁺: 691.

EXAMPLE 137

[0318] Compound 137 was prepared in a manner similar to that described in Example 1.

[0319] LC/MS (M+1)⁺: 612.

EXAMPLE 138

[0320] Compound 138 was prepared in a manner similar to that described in Example 1.

[0321] LC/MS (M+1)⁺: 642.

EXAMPLE 139

[0322] Compound 139 was prepared in a manner similar to that described in Example 1.

[0323] LC/MS (M+1)⁺: 642.

EXAMPLE 140

[0324] Compound 140 was prepared in a manner similar to that described in Example 1.

[0325] LC/MS (M+1)⁺: 682.

EXAMPLE 141

[0326] Compound 141 was prepared in a manner similar to that described in Example 1.

[0327] LC/MS (M+1)⁺: 642.

EXAMPLE 142

[0328] Compound 142 was prepared in a manner similar to that described in Example 1.

[0329] LC/MS (M+1)⁺: 662.8.

EXAMPLE 143

[0330] Compound 143 was prepared in a manner similar to that described in Example 1.

[0331] LC/MS (M+1)⁺: 704.7.

EXAMPLE 144

[0332] Compound 144 was prepared in a manner similar to that described in Example 1.

[0333] LC/MS (M+1)⁺: 667.5.

EXAMPLE 145

[0334] Compound 145 was prepared in a manner similar to that described in Example 1.

[0335] LC/MS (M+1)⁺: 738.4.

EXAMPLE 146

[0336] Compound 146 was prepared in a manner similar to that described in Example 53.

[0337] LC/MS (M+1)⁺: 673.1.

EXAMPLE 147

[0338] Compound 147 was prepared in a manner similar to that described in Example 53.

[0339] LC/MS (M+1)⁺: 665.0.

EXAMPLE 148

[0340] Compound 148 was prepared in a manner similar to that described in Example 53.

[0341] LC/MS (M+1)⁺: 657.4.

EXAMPLE 149

[0342] Compound 149 was prepared in a manner similar to that described in Example 53.

[0343] LC/MS (M+1)⁺: 625.4.

EXAMPLE 150

[0344] Compound 150 was prepared in a manner similar to that described in Example 53.

[0345] LC/MS (M+1)⁺: 635.1.

EXAMPLE 151

[0346] Compound 151 was prepared in a manner similar to that described in Example 1.

[0347] LC/MS (M+1)⁺: 653.4.

EXAMPLE 152

[0348] Compound 152 was prepared in a manner similar to that described in Example 1.

[0349] LC/MS (M+1)⁺: 720.8.

EXAMPLE 153

[0350] Compound 153 was prepared in a manner similar to that described in Example 1.

[0351] LC/MS (M+1)⁺: 682.6.

EXAMPLE 154

[0352] Compound 154 was prepared in a manner similar to that described in Example 1.

[0353] LC/MS (M+1)⁺: 656.6.

EXAMPLE 155

[0354] Compound 155 was prepared in a manner similar to that described in Example 1.

[0355] LC/MS (M+1)⁺: 672.4.

EXAMPLE 156

[0356] Compound 156 was prepared in a manner similar to that described in Example 53.

[0357] LC/MS (M+1)⁺: 725.6.

EXAMPLE 157

[0358] Compound 157 was prepared in a manner similar to that described in Example 1.

[0359] LC/MS (M+1)⁺: 801.4.

EXAMPLE 158

[0360] Compound 158 was prepared following the procedures described below:

[0361] A mixture of 3-[[2-(6-chloro-2-methyl-quinolin-4-ylamino)-ethyl]-(4-methoxy-benzenesulfonyl)-amino]-propionic acid (100 mg) (This compound was prepared in a manner similar to that described in step 1 of Example 53.) and 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (80 mg) was stirred in DMF (2 mL) for 30 minutes at room temperature, followed by addition of 4-amino-N-(2,6-dimethyl-pyrimidin-4-yl)-benzenesulfonamide (64 mg). The reaction mixture was stirred for 3 hours, and then the solvent was evaporated under vacuum. The residue was then quenched with H₂O (2 mL) and extracted with CHCl₃ (10 mL). The combined extract was dried with MgSO₄, concentrated under vacuum, and purified by column chromatography to give compound 158.

[0362] LC/MS (M+1)⁺: 737.8.

EXAMPLE 159

[0363] Compound 159 was prepared in a manner similar to that described in Example 158.

[0364] LC/MS (M+1)⁺: 595.8.

EXAMPLE 160

[0365] Compound 160 was prepared in a manner similar to that described in Example 158.

[0366] LC/MS (M+1)⁺: 637.8.

EXAMPLE 161

[0367] Compound 161 was prepared in a manner similar to that described in Example 158.

[0368] LC/MS (M+1)⁺: 553.9.

EXAMPLE 162

[0369] Compound 162 was prepared in a manner similar to that described in Example 158.

[0370] LC/MS (M+1)⁺: 610.9.

EXAMPLE 163

[0371] Compound 163 was prepared in a manner similar to that described in Example 158.

[0372] LC/MS (M+1)⁺: 660.1.

EXAMPLE 164

[0373] Compound 164 was prepared in a manner similar to that described in Example 158.

[0374] LC/MS (M+1)⁺: 568.9.

EXAMPLE 165

[0375] Compound 165 was prepared in a manner similar to that described in Example 158.

[0376] LC/MS (M+1)⁺: 552.9.

EXAMPLE 166

[0377] Compound 166 was prepared in a manner similar to that described in Example 158.

[0378] LC/MS (M+1)⁺: 609.1.

EXAMPLE 167

[0379] Compound 167 was prepared in a manner similar to that described in Example 158.

[0380] LC/MS (M+1)⁺: 597.1.

EXAMPLE 168

[0381] Compound 168 was prepared in a manner similar to that described in Example 158.

[0382] LC/MS (M+1)⁺: 568.9.

EXAMPLE 169

[0383] Compound 169 was prepared in a manner similar to that described in Example 158.

[0384] LC/MS (M+1)⁺: 594.9.

EXAMPLE 170

[0385] Compound 170 was prepared in a manner similar to that described in Example 158.

[0386] LC/MS (M+1)⁺: 584.1.

EXAMPLE 171

[0387] Compound 171 was prepared in a manner similar to that described in Example 68.

[0388] LC/MS (M+1)⁺: 604.1.

EXAMPLE 172

[0389] Compound 172 was prepared in a manner similar to that described in Example 158.

[0390] LC/MS (M+1)⁺: 604.0.

EXAMPLE 173

[0391] Compound 173 was prepared in a manner similar to that described in Example 158.

[0392] LC/MS (M+1)⁺: 568.1.

EXAMPLE 174

[0393] Compound 174 was prepared in a manner similar to that described in Example 158.

[0394] LC/MS (M+1)⁺: 568.0.

EXAMPLE 175

[0395] Compound 175 was prepared in a manner similar to that described in Example 158.

[0396] LC/MS (M+1)⁺: 582.9.

EXAMPLE 176

[0397] Compound 176 was prepared in a manner similar to that described in Example 158.

[0398] LC/MS (M+1)⁺: 644.9.

EXAMPLE 177

[0399] Compound 177 was prepared in a manner similar to that described in Example 158.

[0400] LC/MS (M+1)⁺: 603.9.

EXAMPLE 178

[0401] Compound 178 was prepared in a manner similar to that described in Example 158.

[0402] LC/MS (M+1)⁺: 583.9.

EXAMPLE 179

[0403] Compound 179 was prepared in a manner similar to that described in Example 158.

[0404] LC/MS (M+1)⁺: 568.9.

EXAMPLE 180

[0405] Compound 180 was prepared in a manner similar to that described in Example 158.

[0406] LC/MS (M+1)⁺: 554.1.

EXAMPLE 181

[0407] Compound 181 was prepared in a manner similar to that described in Example 158.

[0408] LC/MS (M+1)⁺: 569.1.

EXAMPLE 182

[0409] Compound 182 was prepared in a manner similar to that described in Example 158.

[0410] LC/MS (M+1)⁺: 599.1.

EXAMPLE 183

[0411] Compound 183 was prepared in a manner similar to that described in Example 158.

[0412] LC/MS (M+1)⁺: 559.1.

EXAMPLE 184

[0413] Compound 184 was prepared in a manner similar to that described in Example 158.

[0414] LC/MS (M+1)⁺: 620.1.

EXAMPLE 185

[0415] Compound 185 was prepared in a manner similar to that described in Example 158.

[0416] LC/MS (M+1)⁺: 604.1.

EXAMPLE 186

[0417] Compound 186 was prepared in a manner similar to that described in Example 158.

[0418] LC/MS (M+1)⁺: 603.9.

EXAMPLE 187

[0419] Compound 187 was prepared in a manner similar to that described in Example 158.

[0420] LC/MS (M+1)⁺: 570.9.

EXAMPLE 188

[0421] Compound 188 was prepared in a manner similar to that described in Example 158.

[0422] LC/MS (M+1)⁺: 601.9.

EXAMPLE 189

[0423] Compound 189 was prepared in a manner similar to that described in Example 158.

[0424] LC/MS (M+1)⁺: 613.1.

EXAMPLE 190

[0425] Compound 190 was prepared in a manner similar to that described in Example 158.

[0426] LC/MS (M+1)⁺: 682.1.

EXAMPLE 191

[0427] Compounds 1-190 were tested for their efficacy in blocking activation of CXCR3 using a DELFIA GTP-binding kit (Wallac Oy, Turku, Finland). The DELFIA GTP-binding assay is a time-resolved fluorometric assay based on GDP-GTP exchange on G-protein subunits followed by activation of a G protein-coupled receptor by its agonists. Eu-GTP, obtained from Wallac Oy, was used in this assay to allow monitoring of agonist-dependent activation of G-protein. Stimulation of CXCR3 by interferon-α inducible protein 10 (IP-10) leads to the replacement of GDP by GTP on the α-subunit of G-protein. This GTP-Gα complex represents the activated form of G-protein. Eu-GTP, a non-hydrolysable analog of GTP, can be used to quantify the amount of activated G-protein. (Peltonen et al., Eur. J. Pharmacol. (1998) 355:275.)

[0428] Plasma membrane of CXCR3-expressing HEK293 cells was suspended in an assay buffer (50 mM NaCl, 100 μg/mL saponin, 3 mM MgCl₂, 3 μM GDP, 5% BSA, 50 mM HEPES, pH 7.4). An aliquot (4 μg protein) was added to each well of an AcroPlate (Pall Life Sciences, Ann Arbor, Mich.). After the addition of the test compounds (10 μM in 0.1% DMSO) and IP-10 (4 nM in the assay buffer), the assay plate was incubated in the dark at room temperature with slow shaking for 10 minutes. Eu-GTP was added to each well and the plate was incubated again for 60 minutes. The assay was terminated by washing the plate twice with a wash solution provided in the assay kit. Binding of Eu-GTP was determined based on the fluorescence signal from a Victor 2 multi-label reader.

[0429] Unexpectedly, 92 compounds showed IC₅₀ values lower than 1 μM, 33 compounds showed IC₅₀ values between 1 μM and 5 μM, and 30 compounds showed IC₅₀ values between 5 μM and 10 μM.

OTHER EMBODIMENTS

[0430] All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.

[0431] From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the scope of the following claims. 

What is claimed is:
 1. A method for treating an inflammatory or immune disease, comprising administering to a subject in need thereof an effective amount of a compound of formula (I):

wherein each

is a single bond or a double bond; provided that if one

is a double bond, its neighboring

is not a double bond; each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═, —CR_(a)—, —N═, —N—, —S—, —O—, or a single bond; at most one of

X₁—,

X₂—,

X₃—, and

X₄— being a single bond, and at most two of

X₁—,

X₂—,

X₃—, and

X₄— being —N═, —N—, —S—, or —O—; each of R₁ and R₂, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(b)R_(b)′, —C(O)—OR_(b), —OC(O)—R_(b), —C(O)—R_(b), or halogen; or R₁ and R₂ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; each of R₃ and R₄, independently, is H or -A-N(B)-D; and each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, NO₂, CN, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(c)R_(c)′, —C(O)—OR_(c), —OC(O)—R_(c), —C(O)—R_(c), halogen, or deleted; or R₅ and R₆ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₆ and R₇ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₇ and R₈ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₅ is deleted,

X₁— is —N═, —S—, —O—, or a single bond; if R₆ is deleted,

X₂— is —N═, —S—, —O—, or a single bond; if R₇ is deleted,

X₃— is —N═, —S—, —O—, or a single bond; and if R₈ is deleted,

X₄— is —N═, —S—, —O—, or a single bond; in which A is C₁-C₁₂ alkyl optionally containing 1-6 heteroatoms, C₂-C₁₂ alkenyl optionally containing 1-6 heteroatoms, C₂-C₁₂ alkynyl optionally containing 1-6 heteroatoms, aryl, heteroaryl, C₁-C₁₀ alkylsulfonyl, arylsulfonyl, C₁-C₁₀ alkylcarbonyl containing 1-6 heteroatoms, C₂-C₂₀ alkylaryl optionally containing 1-6 heteroatoms, C₂-C₂₀ arylalkyl optionally containing 1-6 heteroatoms, C₂-C₂₀ alkylheteroaryl containing 1-6 heteroatoms, or C₂-C₂₀ heteroarylalkyl containing 1-6 heteroatoms; B is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl; or B and A together are C₅-C₇ heterocycloalkyl or heteroaryl; and D is H, aryl, heteroaryl, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, —C(O)—R_(d), —SO₂—R_(d), —C(S)—R_(d), —C(O)—NR_(d)R_(d)′, —C(O)—OR_(d), —OC(O)—R_(d), —C(O)—SR_(d), or —SC(O)—R_(d); or D and A together are C₅-C₇ heterocycloalkyl or heteroaryl; each of R_(a), R_(b), R_(b)′, R_(c), R_(c)′, R_(d), and R_(d)′, independently, being H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl; or R_(d) and R_(d)′ together being C₅-C₇ heterocycloalkyl; or a salt thereof.
 2. The method of claim 1, wherein D is of formula (II),

wherein each

is a single bond or a double bond; provided that if one

is a double bond, its neighboring

is not a double bond; each of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, independently, is —C═, —CR_(e)—, —N═, —N—, —S—, —O—, or a single bond; at most one of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, being a single bond, and at most two of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, being —N═, —N—, —S—, or —O—; each of R₁′ and R₂′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(f)R_(f)′, —C(O)—OR_(f), —OC(O)—R_(f), —C(O)—R_(f), or halogen; or R₁′ and R₂′ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, NO₂, CN, C₁-C₆ alkylamino, C₁-C₁₂dialkylamino, arylamino, diarylamino, —C(O)—NR_(g)R_(g)′, —C(O)—OR_(g), —OC(O)—R_(g), —C(O)—R_(g), halogen, or deleted; or R₃′ and R₄′ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₄′ and R₅′ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₅′ and R₆′ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₃′ is deleted,

X₁′— is —N═, —S—, —O—, or a single bond; if R₄′ is deleted,

X₂′— is —N═, —S—, —O—, or a single bond; if R₅′ is deleted,

X₃′— is —N═, —S—, —O—, or a single bond; and if R₆′ is deleted,

X₄′— is —N═, —S—, —O—, or a single bond; in which each of R_(e), R_(f), R_(f)′, R_(g), and R_(g)′, independently, being H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl.
 3. The method of claim 1, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═, —CR_(a)—, —N═, —N—, —S—, or a single bond; each of R₁ and R₂, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylamino, diarylamino, —C(O)—NR_(b)R_(b)′, or —C(O)—R_(b); or R₁ and R₂ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocyclolkyl, C₅-C₈ heterocycloalkenyl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NO₂, —C(O)—NR_(c)R_(c)′, —C(O)—R_(c), halogen, or deleted; or R₆ and R₇ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₅ is deleted,

X₁— is —N═, —S—, or a single bond; if R₆ is deleted,

X₂— is —N═, —S—, or a single bond; if R₇ is deleted,

X₃— is —N═, —S—, or a single bond; and if R₈ is deleted,

X₄— is —N═, —S—, or a single bond; B is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, or heteroaryl; or B and A together are C₅-C₇ heterocycloalkyl or heteroaryl; D is H, aryl, heteroaryl, C₁-C₈ alkyl, C₃-C₈ heterocycloalkyl, or —C(O)—R_(d); or D and A together are C₅-C₇ heterocycloalkyl or heteroaryl; and each of R_(a), R_(b), R_(b)′, R_(c), R_(c)′, R_(d), and R_(d)′, independently, is H, C₅-C₈ cycloalkenyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl.
 4. The method of claim 3, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═, —CR_(a)—, or —N═; each of R₁ and R₂, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, or C₁-C₆ alkylthio; or R₁ and R₂ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ heterocycloalkyl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, halogen, or deleted; or R₆ and R₇ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₅ is deleted,

X₁— is —N═; if R₆ is deleted,

X₂— is —N═; if R₇ is deleted,

X₃— is —N═; and if R₈ is deleted,

X₄— is —N═; A is C₁-C₁₂ alkyl optionally containing 1-6 heteroatoms, C₂-C₁₂ alkenyl optionally containing 1-6 heteroatoms, C₂-C₁₂ alkynyl optionally containing 1-6 heteroatoms, aryl, C₁-C₁₀ alkylsulfonyl, arylsulfonyl, C₁-C₁₀ alkylcarbonyl containing 1-6 heteroatoms, C₂-C₂₀ alkylaryl optionally containing 1-6 heteroatoms, or C₂-C₂₀ arylalkyl optionally containing 1-6 heteroatoms; D is H, aryl, heteroaryl, C₁-C₈ alkyl, C₃-C₈ heterocycloalkyl, or —C(O)—R_(d); and each of R_(a), R_(b), R_(b)′, R_(c), R_(c)′, R_(d), and R_(d)′, independently, is H, aryl, or heteroaryl.
 5. The method of claim 4, wherein A is C₁-C₁₂ alkyl, arylsulfonyl, C₁-C₁₀ alkylcarbonyl containing 1-6 heteroatoms, C₂-C₂₀ arylalkyl, or A and B together are heteroaryl.
 6. The method of claim 5, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═; each of R₁ and R₂, independently, is H or C₁-C₈ alkyl; or R₁ and R₂ together are C₅-C₈ cycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₁-C₆ alkoxy, or halogen; and B is H or B and A together are heteroaryl.
 7. The method of claim 4, wherein D is of formula (II),

wherein each

is a single bond or a double bond; provided that if one

is a double bond, its neighboring

is not a double bond; each of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, independently, is —C═, —CR_(e)—, or —N═; at most two of

X₁′—,

X₂′—,

X₃′—, and

X₄′— being —N═; each of R₁′ and R₂′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, or C₁-C₆ alkylthio; or R₁′ and R₂′ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; and each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ heterocycloalkyl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, or halogen; or R₄′ and R₅′ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; in which R_(e) is H, aryl, or heteroaryl.
 8. The method of claim 7, wherein A is C₁-C₁₂ alkyl.
 9. The method of claim 7, wherein A is C₁-C₁₂ alkyl containing 1-6 heteroatoms and optionally substituted with sulfonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl.
 10. The method of claim 7, wherein A is C₂-C₂₀ alkylaryl optionally containing 1-6 heteroatoms.
 11. The method of claim 7, wherein A is aryl, or A and B together are heteroaryl.
 12. The method of claim 8, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═; each of R₁ and R₂, independently, is H, C₁-C₈ alkyl, or aryl; or R₁ and R₂ together are C₅-C₈ cycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₃-C₈ heterocycloalkyl, OH, C₁-C₆ alkoxy, aryloxy, C₁-C₆ alkylthio, or halogen; B is H or C₁-C₈ alkyl; each of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, independently, is —C═; each of R₁′ and R₂′, independently, is H, C₁-C₈ alkyl, or aryl; or R₁′ and R₂′together are C₅-C₈ cycloalkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, C₃-C₈ heterocycloalkyl, OH, C₁-C₆ alkoxy, aryloxy, C₁-C₆ alkylthio, or halogen.
 13. The method of claim 9, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═; each of R₁ and R₂, independently, is H or C₁-C₈ alkyl; or R₁ and R₂ together are C₅-C₈ cycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₁-C₆ alkoxy, aryloxy, C₁-C₆ alkylthio, or halogen; B is H; each of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, independently, is —C═; each of R₁′ and R₂′, independently, is H or C₁-C₈ alkyl; or R₁′ and R₂′ together are C₅-C₈ cycloalkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, C₁-C₆ alkoxy, aryloxy, C₁-C₆ alkylthio, or halogen.
 14. The method of claim 10, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═; each of R₁ and R₂, independently, is H or C₁-C₈ alkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₁-C₆ alkoxy, aryloxy, or halogen; B is H; each of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, independently, is —C═; each of R₁′ and R₂′, independently, is H or C₁-C₈ alkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, C₁-C₆ alkoxy, aryloxy, or halogen.
 15. The method of claim 11, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═; each of R₁ and R₂, independently, is H or C₁-C₈ alkyl; each of R₅, R₆, R₇, and R₈, independently, is H or C₁-C₈ alkyl; B is H; or B and A together are heteroaryl; each of

X₁′—,

X₂′—,

X₃′—, and

X₄—, independently, is —C═; each of R₁′ and R₂′, independently, is H or C₁-C₈ alkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H or C₁-C₈ alkyl.
 16. A compound of formula (I):

wherein each

is a single bond or a double bond; provided that if one

is a double bond, its neighboring

is not a double bond; each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═, —CR_(a)—, —N═, —N—, —S—, —O—, or a single bond; at most one of

X₁—,

X₂—,

X₃—, and

X₄— being a single bond and at most two of

X₁—,

X₂—,

X₃—, and

X₄— being —N═, —N—, —S—, or —O—; each of R₁ and R₂, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(b)R_(b)′, —OC(O)—R_(b), —C(O)—R_(b), or halogen; or R₁ and R₂ together are C₅-C₈ heterocycloalkyl; each of R₃ and R₄, independently, is H or -A-N(B)-D; at most one of R₃ and R₄ being H; and each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, NO₂, CN, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(c)R_(c)′, —C(O)—OR_(c), —OC(O)—R_(c), —C(O)—R_(c), halogen, or deleted; or R₅ and R₆ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₆ and R₇ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₇ and R₈ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₅ is deleted,

X₁— is —N═, —S—, —O—, or a single bond; if R₆ is deleted,

X₂— is —N═, —S—, —O—, or a single bond; if R₇ is deleted,

X₃— is —N═, —S—, —O—, or a single bond; and if R₈ is deleted,

X₄— is —N═, —S—, —O—, or a single bond; in which A is C₁-C₁₂ alkyl optionally containing 1-6 heteroatoms, C₂-C₁₂ alkenyl optionally containing 1-6 heteroatoms, C₂-C₁₂ alkynyl optionally containing 1-6 heteroatoms, aryl, heteroaryl, C₁-C₁₀ alkylsulfonyl, arylsulfonyl, C₁-C₁₀ alkylcarbonyl containing 1-6 heteroatoms, C₂-C₂₀ alkylaryl optionally containing 1-6 heteroatoms, C₂-C₂₀ arylalkyl optionally containing 1-6 heteroatoms, C₂-C₂₀ alkylheteroaryl containing 1-6 heteroatoms, or C₂-C₂₀ heteroarylalkyl containing 1-6 heteroatoms; B is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl; or B and A together are heteroaryl; and D is H, aryl, heteroaryl, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, —C(O)—R_(d), —SO₂—R_(d), —C(S)—R_(d), —C(O)—NR_(d)R_(d)′, —C(O)—OR_(d), —OC(O)—R_(d), —C(O)—SR_(d), or —SC(O)—R_(d); or D and A together are heteroaryl; each of R_(a), R_(b), R_(b)′, R_(c), R_(c)′, R_(d), and R_(d)′, independently, being H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl; or R_(d) and R_(d)′ together being C₅-C₇ heterocycloalkyl; or a salt thereof.
 17. The compound of claim 16, wherein D is of formula (II),

wherein each

is a single bond or a double bond; provided that if one

is a double bond, its neighboring

is not a double bond; each of

X₁′—,

X₂′—,

X₃′—, and

X 4′—, independently, is —C═, —CR_(e)—, —N═, —N—, —S—, —O—, or a single bond; at most one of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, being a single bond, and at most two of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, being —N═, —N—, —S—, or —O—; each of R₁′ and R₂′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(f)R_(f)′, —OC(O)—R_(f), —C(O)—R_(f), or halogen; or R₁′ and R₂′ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, NO₂, CN, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(g)R_(g)′, —C(O)—OR_(g), —OC(O)—R_(g), —C(O)—R_(g), halogen, or deleted; or R₃′ and R₄′ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₄′ and R₅′ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₅′ and R₆′ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₃′is deleted,

X₁′— is —N═, —S—, —O—, or a single bond; if R₄′ is deleted,

X₂′— is —N═, —S—, —O—, or a single bond; if R₅′ is deleted,

X₃′— is —N═, —S—, —O—, or a single bond; and if R₆′ is deleted,

X₄′— is —N═, —S—, —O—, or a single bond; in which each of R_(e), R_(f), R_(f)′, R_(g), and R_(g)′, independently, being H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl.
 18. The compound of claim 16, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═, —CR_(a)—, —N═, —N—, —S—, or a single bond; each of R₁ and R₂, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylamino, diarylamino, —C(O)—NR_(b)R_(b)′, or —C(O)—R_(b); or R₁ and R₂ together are C₅-C₈ heterocycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NO₂, —C(O)—NR_(c)R_(c)′, —C(O)—R_(c), halogen, or deleted; or R₆ and R₇ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₅ is deleted,

X₁— is —N═, —S—, or a single bond; if R₆ is deleted,

X₂— is —N═, —S—, or a single bond; if R₇ is deleted,

X₃— is —N═, —S—, or a single bond; and if R₈ is deleted,

X₄— is —N═, —S—, or a single bond; B is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, or heteroaryl; or B and A together are heteroaryl; D is H, aryl, heteroaryl, C₃-C₈ heterocycloalkyl, or C₁-C₈ alkyl; or D and A together are heteroaryl; and each of R_(a), R_(b), R_(b)′, R_(c), R_(c)′, R_(d), and R_(d)′, independently, is H, C₅-C₈ cycloalkenyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl.
 19. The compound of claim 18, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═, —CR_(a)—, or —N═; each of R₁ and R₂, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, or C₁-C₆ alkylthio; or R₁ and R₂ together are C₅-C₈ heterocycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ heterocycloalkyl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, halogen, or deleted; or R₆ and R₇ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₅ is deleted,

X₁— is —N═; if R₆ is deleted,

X₂— is —N═; if R₇ is deleted,

X₃— is —N═; and if R₈ is deleted,

X₄— is —N═; A is C₁-C₁₂ alkyl optionally containing 1-6 heteroatoms, C₂-C₁₂ alkenyl optionally containing 1-6 heteroatoms, C₂-C₁₂ alkynyl optionally containing 1-6 heteroatoms, aryl, C₁-C₁₀ alkylsulfonyl, arylsulfonyl, C₁-C₁₀ alkylcarbonyl containing 1-6 heteroatoms, C₂-C₂₀ alkylaryl optionally containing 1-6 heteroatoms, or C₂-C₂₀ arylalkyl optionally containing 1-6 heteroatoms; D is H, aryl, heteroaryl, C₃-C₈ heterocycloalkyl, or C₁-C₈ alkyl; and each of R_(a), R_(b), R_(b)′, R_(c), R_(c)′, R_(d), and R_(d)′, independently, is H, aryl, or heteroaryl.
 20. The method of claim 19, wherein A is C₁-C₁₂ alkyl, arylsulfonyl, C₁-C₁₀ alkylcarbonyl containing 1-6 heteroatoms, C₂-C₂₀ arylalkyl, or A and B together are heteroaryl.
 21. The method of claim 20, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═; each of R₁ and R₂, independently, is H or C₁-C₈ alkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₁-C₆ alkoxy, or halogen; and B is H or B and A together are heteroaryl.
 22. The compound of claim 21, wherein the compound is compound 68 or compound
 70. 23. The compound of claim 19, wherein D is of formula (II),

wherein each

is a single bond or a double bond; provided that if one

is a double bond, its neighboring

is not a double bond; each of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, independently, is —C═, —CR_(e)—, or —N═; at most two of

X₁′—,

X₂′—,

X₃′—, and

X₄′— being —N═; each of R₁′ and R₂′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, or C₁-C₆ alkylthio; or R₁′ and R₂′ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; and each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ heterocycloalkyl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, or halogen; or R₄′ and R₅′ together are C₅-C₇ heterocycloalkyl in which R_(e) is H, aryl, or heteroaryl.
 24. The compound of claim 23, wherein A is C₁-C₁₂ alkyl.
 25. The compound of claim 23, wherein A is C₁-C₁₂ alkyl containing 1-6 heteroatoms and optionally substituted with sulfonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl.
 26. The compound of claim 23, wherein A is C₂-C₂₀ alkylaryl optionally containing 1-6 heteroatoms.
 27. The compound of claim 23, wherein A is aryl, or A and B together are heteroaryl.
 28. The compound of claim 24, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═; each of R₁ and R₂, independently, is H, C₁-C₈ alkyl, or aryl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₃-C₈ heterocycloalkyl, OH, C₁-C₆ alkoxy, aryloxy, C₁-C₆ alkylthio, or halogen; B is H or C₁-C₈ alkyl; each of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, independently, is —C═; each of R₁′ and R₂′, independently, is H, C_(1-C) ₈ alkyl, or aryl; or R₁′ and R₂′ together are C₅-C₈ cycloalkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, C₃-C₈ heterocycloalkyl, OH, C₁-C₆ alkoxy, aryloxy, C₁-C₆ alkylthio, or halogen.
 29. The compound of claim 28, wherein the compound is one of the compounds 1-3, 5, 11-12, 19, 23, 30, and 53-55.
 30. The compound of claim 25, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═; each of R₁ and R₂, independently, is H or C₁-C₈ alkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₁-C₆ alkoxy, aryloxy, C₁-C₆ alkylthio, or halogen; B is H; each of

X₁′—,

X₂′—,

X₃—, and

X₄—, independently, is —C═; each of R₁′ and R₂′, independently, is H or C₁-C₈ alkyl; or R₁′ and R₂′ together are C₅-C₈ cycloalkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, C_(-C) ₆ alkoxy, aryloxy, C₁-C₆ alkylthio, or halogen.
 31. The compound of claim 30, wherein the compound is one of compounds 31, 41-44, and
 51. 32. The compound of claim 26, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═; each of R₁ and R₂, independently, is H or C₁-C₈ alkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₁-C₆ alkoxy, aryloxy, or halogen; B is H; each of

X₁′—,

X₂′—,

X₃′—, and

X₄′—,independently, is —C═; each of R₁′ and R₂′, independently, is H or C₁-C₈ alkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, C₁-C₆ alkoxy, aryloxy, or halogen.
 33. The compound of claim 32, wherein the compound is one of compounds 38 and 59-63.
 34. The compound of claim 27, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═; each of R₁ and R₂, independently, is H or C₁-C₈ alkyl; each of R₅, R₆, R₇, and R₈, independently, is H or C₁-C₈ alkyl; B is H; or B and A together are heteroaryl; each of

X₁′—,

X₂′—,

X₃′—, and

X₄—, independently, is —C═; each of R₁′ and R₂′, independently, is H or C₁-C₈ alkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H or C₁-C₈ alkyl.
 35. The compound of claim 34, wherein the compound is compound
 36. 36. A compound of formula (I):

wherein each

is a single bond or a double bond; provided that if one

is a double bond, its neighboring

is not a double bond; each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═, —CR_(a)—, —N═, —N—, —S—, —O—, or a single bond; at most one of

X₁—,

X₂—,

X₃—, and

X₄— being a single bond and at most two of

X₁—,

X₂—,

X₃—, and

X₄— being —N═, —N—, —S—, or —O—; each of R₁and R₂, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(b)R_(b)′, —OC(O)—R_(b), —C(O)—R_(b), or halogen; or R₁ and R₂ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; each of R₃ and R₄, independently, is H or -A-N(B)-D; at most one of R₃ and R₄ being H; and each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, NO₂, CN, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(c)R_(c)′, —C(O)—OR_(c), —OC(O)—R_(c), —C(O)—R_(c), or deleted; or R₅ and R₆ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₆ and R₇ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₇ and R₈ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₅ is deleted,

X₁— is —N═, —S—, —O—, or a single bond; if R₆ is deleted,

X₂— is —N═, —S—, —O—, or a single bond; if R₇ is deleted,

X₃— is —N═, —S—, —O—, or a single bond; and if R₈ is deleted,

X₄— is —N═, —S—, —O—, or a single bond; and further provided that not all of R₅, R₆, R₇, and R₈ are H; in which A is C₁-C₁₂ alkyl optionally containing 1-6 heteroatoms, C₂-C₁₂ alkenyl optionally containing 1-6 heteroatoms, C₂-C₁₂ alkynyl optionally containing 1-6 heteroatoms, aryl, heteroaryl, C₁-C₁₀ alkylsulfonyl, arylsulfonyl, C₁-C₁₀ alkylcarbonyl containing 1-6 heteroatoms, C₂-C₂₀ alkylaryl optionally containing 1-6 heteroatoms, C₂-C₂₀ arylalkyl optionally containing 1-6 heteroatoms, C₂-C₂₀ alkylheteroaryl containing 1-6 heteroatoms, or C₂-C₂₀ heteroarylalkyl containing 1-6 heteroatoms; B is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl; or B and A together are heteroaryl; and D is H, aryl, heteroaryl, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, —C(O)—R_(d), —SO₂—R_(d), —C(S)—R_(d), —C(O)—NR_(d)R_(d)′, —C(O)—OR_(d), —OC(O)—R_(d), —C(O)—SR_(d), or —SC(O)—R_(d); or D and A together are heteroaryl; each of R_(a), R_(b), R_(b)′, R_(c), R_(c)′, R_(d), and R_(d)′, independently, being H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl; or R_(d) and R_(d)′ together being C₅-C₇ heterocycloalkyl; or a salt thereof.
 37. The compound of claim 36, wherein D is of formula (II),

wherein each

is a single bond or a double bond; provided that if one

is a double bond, its neighboring

is not a double bond; each of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, independently, is —C═, —CR_(e)—, —N═, —N—, —S—, —O—, or a single bond; at most one of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, being a single bond, and at most two of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, being —N═, —N—, —S—, or —O—; each of R₁′ and R₂′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(f)R_(f)′, —OC(O)—R_(f), —C(O)—R_(f), or halogen; or R₁′ and R₂′ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, NO₂, CN, C₁-C₆ alkylamino, C₁-C₁₂dialkylamino, arylamino, diarylamino, —C(O)—NR_(g)R_(g)′, —OC(O)—R_(g), —C(O)—R_(g), or deleted; or R₃′ and R₄′ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₄′ and R₅′ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₅′ and R₆′ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₃′ is deleted,

X₁′— is —N═, —S—, —O—, or a single bond; if R₄′ is deleted,

X₂′— is —N═, —S—, —O—, or a single bond; if R₅′ is deleted,

X₃′— is —N═, —S—, —O—, or a single bond; if R₆′ is deleted,

X₄′— is —N═, —S—, —O—, or a single bond; and further provided that not all of R₃′, R₄′, R₅′, and R₆′are H; in which each of R_(e), R_(f), R_(f)′, R_(g), and R_(g)′, independently, being H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl.
 38. The compound of claim 36, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═, —CR_(a)—, —N═, —N—, —S—, or a single bond; each of R₁ and R₂, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylamino, diarylamino, —C(O)—NR_(b)R_(b)′, or —C(O)—R_(b); or R₁ and R₂ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NO₂, —C(O)—NR_(c)R_(c)′, —C(O)—R_(c), or deleted; or R₆ and R₇ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₅ is deleted,

X₁— is —N═, —S—, or a single bond; if R₆ is deleted,

X₂— is —N═, —S—, or a single bond; if R₇ is deleted,

X₃— is —N═, —S—, or a single bond; and if R₈ is deleted,

X₄— is —N═, —S—, or a single bond; B is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, or heteroaryl; or B and A together are heteroaryl; D is H, aryl, heteroaryl, C₁-C₈ alkyl, C₃-C₈ heterocycloalkyl, or —C(O)—R_(d); or D and A together are heteroaryl; and each of R_(a), R_(b), R_(b)′, R_(c), R_(c)′, R_(d), and R_(d)′, independently, is H, C₅-C₈ cycloalkenyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl.
 39. The compound of claim 38, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═, —CR_(a)—, or —N═; each of R₁ and R₂, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, or C₁-C₆ alkylthio; or R₁ and R₂ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ heterocycloalkyl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, or deleted; or R₆ and R₇ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₅ is deleted,

X₁— is —N═; if R₆ is deleted,

X₂— is —N═; if R₇ is deleted,

X₃— is —N═; and if R₈ is deleted,

X₄— is —N═; A is C₁-C₁₂ alkyl optionally containing 1-6 heteroatoms, C₂-C₁₂ alkenyl optionally containing 1-6 heteroatoms, C₂-C₁₂ alkynyl optionally containing 1-6 heteroatoms, aryl, C₁-C₁₀ alkylsulfonyl, arylsulfonyl, C₁-C₁₀ alkylcarbonyl containing 1-6 heteroatoms, C₂-C₂₀ alkylaryl optionally containing 1-6 heteroatoms, or C₂-C₂₀ arylalkyl optionally containing 1-6 heteroatoms; D is H, aryl, heteroaryl, C₁-C₈ alkyl, C₃-C₈ heterocycloalkyl, or —C(O)—R_(d); and each of R_(a), R_(b), R_(b)′, R_(c), R_(c)′, R_(d), and R_(d)′, independently, is H, aryl, or heteroaryl.
 40. The method of claim 39, wherein A is C₁-C₁₂ alkyl.
 41. The method of claim 40, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═; R₁ and R₂ together are C₅-C₈ cycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H or C₁-C₈ alkyl; B is H; and D is H, heteroaryl, or —C(O)—R_(d).
 42. The compound of claim 41, wherein the compound is compound 72 or compound
 73. 43. The compound of claim 39, wherein D is of formula (II),

wherein each

is a single bond or a double bond; provided that if one

is a double bond, its neighboring

is not a double bond; each of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, independently, is —C═, —CR_(e)—, or —N═; at most two of

X₁′—,

X₂′—,

X₃′—, and

X₄′— being —N═; each of R₁′ and R₂′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, or C₁-C₆ alkylthio; or R₁′ and R₂′ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; and each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ heterocycloalkyl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, or arylthio; or R₄′ and R₅′ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl in which R_(e) is H, aryl, or heteroaryl.
 44. The compound of claim 43, wherein A is C₁-C₁₂ alkyl.
 45. The compound of claim 43, wherein A is C₁-C₁₂ alkyl containing 1-6 heteroatoms and optionally substituted with sulfonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl.
 46. The compound of claim 44, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═; R₁ and R₂ together are C₅-C₈ cycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₁-C₆ alkoxy, or halogen; B is H; each of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, independently, is —C ; each of R₁′ and R₂′, independently, is H or C₁-C₈ alkyl; or R₁′ and R₂′ together are C₅-C₈ cycloalkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, or C₁-C₆ alkoxy.
 47. The compound of claim 46, wherein the compound is one of compounds 25-28 and 57-58.
 48. The compound of claim 45, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═; R₁ and R₂ together are C₅-C₈ cycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H or C₁-C₈ alkyl; B is H; each of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, independently, is —C═; R₁′ and R₂′ together are C₅-C₈ cycloalkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H or C₁-C₈ alkyl.
 49. A pharmaceutical composition comprising a compound of formula (I):

wherein each

is a single bond or a double bond; provided that if one

is a double bond, its neighboring

is not a double bond; each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═, —CR_(a)—, —N═, —N—, —S—, —O—, or a single bond; at most one of

X₁—,

X₂—,

X₃—, and

X₄— being a single bond and at most two of

X₁—,

X₂—,

X₃—, and

X₄— being —N═, —N—, —S—, or —O—; each of R₁ and R₂, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(b)R_(b)′, —C(O)—OR_(b), —OC(O)—R_(b), —C(O)—R_(b), or halogen; or R₁ and R₂ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; each of R₃ and R₄, independently, is H or -A-N(B)-D; and each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, NO₂, CN, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(c)R_(c)′, —C(O)—OR_(c), —OC(O)—R_(c), —C(O)—R_(c), halogen, or deleted; or R₅ and R₆ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₆ and R₇ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₇ and R₈ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₅ is deleted,

X₁— is —N═, —S—, —O—, or a single bond; if R₆ is deleted,

X₂— is —N═, —S—, —O—, or a single bond; if R₇ is deleted,

X₃— is —N═, —S—, —O—, or a single bond; and if R₈ is deleted,

X₄— is —N═, —S—, —O—, or a single bond; in which A is C₁-C₁₂ alkyl optionally containing 1-6 heteroatoms, C₂-C₁₂ alkenyl optionally containing 1-6 heteroatoms, C₂-C₁₂ alkynyl optionally containing 1-6 heteroatoms, aryl, heteroaryl, C₁-C₁₀ alkylsulfonyl, arylsulfonyl, C₁-C₁₀ alkylcarbonyl containing 1-6 heteroatoms, C₂-C₂₀ alkylaryl optionally containing 1-6 heteroatoms, C₂-C₂₀ arylalkyl optionally containing 1-6 heteroatoms, C₂-C₂₀ alkylheteroaryl containing 1-6 heteroatoms, or C₂-C₂₀ heteroarylalkyl containing 1-6 heteroatoms; B is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl; or B and A together are C₅-C₇ heterocycloalkyl or heteroaryl; and D is H, aryl, heteroaryl, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, —C(O)—R_(d), —SO₂—R_(d), —C(S)—R_(d), —C(O)—NR_(d)R_(d)′, —C(O)—OR_(d), —OC(O)—R_(d), —C(O)—SR_(d), or —SC(O)—R_(d); or D and A together are C₅-C₇ heterocycloalkyl or heteroaryl; each of R_(a), R_(b), R_(b)′, R_(c), R_(c)′, R_(d), and R_(d)′, independently, being H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl; or R_(d) and R_(d)′ together being C₅-C₇ heterocycloalkyl; or a salt thereof; and a pharmaceutically acceptable carrier.
 50. The composition of claim 49, wherein D is of formula (II),

wherein each

is a single bond or a double bond; provided that if one

is a double bond, its neighboring

is not a double bond; each of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, independently, is —C═, —CR_(e)—, —N═, —N—, —S—, —O—, or a single bond; at most one of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, being a single bond, and at most two of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, being —N═, —N—, —S—, or —O—; each of R₁′ and R₂′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(f)R_(f)′, —C(O)—OR_(f), —OC(O)—R_(f), —C(O)—R_(f), or halogen; or R₁′ and R₂′ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, heteroaryl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NH₂, NO₂, CN, C₁-C₆ alkylamino, C₁-C₁₂ dialkylamino, arylamino, diarylamino, —C(O)—NR_(g)R_(g)′, —C(O)—OR_(g), —OC(O)—R_(g), —C(O)—R_(g), halogen, or deleted; or R₃′ and R₄′ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₄′ and R₅′ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; or R₅′ and R₆′ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₃′is deleted,

X₁′— is —N═, —S—, —O—, or a single bond; if R₄′ is deleted,

X₂′— is —N═, —S—, —O—, or a single bond; if R₅′ is deleted,

X₃′— is —N═, —S—, —O—, or a single bond; and if R₆′ is deleted,

X₄′— is —N═, —S—, —O—, or a single bond; in which each of R_(e), R_(f), R_(f)′, R_(g), and R_(g)′, independently, being H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl.
 51. The composition of claim 49, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═, —CR_(a)—, —N═, —N—, —S—, or a single bond; each of R₁ and R₂, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylamino, diarylamino, —C(O)—NR_(b)R_(b)′, or —C(O)—R_(b); or R₁ and R₂ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ heterocycloalkyl, C₅-C₈ heterocycloalkenyl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, NO₂, —C(O)—NR_(c)R_(c)′, —C(O)—R_(c), halogen, or deleted; or R₆ and R₇ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₅ is deleted,

X₁— is —N═, —S—, or a single bond; if R₆ is deleted,

X₂— is —N═, —S—, or a single bond; if R₇ is deleted,

X₃— is —N═, —S—, or a single bond; and if R₈ is deleted,

X₄— is —N═, —S—, or a single bond; B is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, or heteroaryl; or B and A together are C₅-C₇ heterocycloalkyl or heteroaryl; D is H, aryl, heteroaryl, C₁-C₈ alkyl, C₃-C₈ heterocycloalkyl, or —C(O)—R_(d); or D and A together are C₅-C₇ heterocycloalkyl or heteroaryl; and each of R_(a), R_(b), R_(b)′, R_(c), R_(c)′, R_(d), and R_(d)′, independently, being H, C₅-C₈ cycloalkenyl, C₅-C₈ heterocycloalkenyl, aryl, or heteroaryl.
 52. The composition of claim 51, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═, —CR_(a)—, or —N═; each of R₁ and R₂, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, or C₁-C₆ alkylthio; or R₁ and R₂ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ heterocycloalkyl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, halogen, or deleted; or R₆ and R₇ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl; provided that if R₅ is deleted,

X₁— is —N═; if R₆ is deleted,

X₂— is —N═; if R₇ is deleted,

X₃— is —N═; and if R₈ is deleted,

X₄— is —N═; A is C_(-C) ₁₂ alkyl optionally containing 1-6 heteroatoms, C₂-C₁₂ alkenyl optionally containing 1-6 heteroatoms, C₂-C₁₂ alkynyl optionally containing 1-6 heteroatoms, aryl, C₁-C₁₀ alkylsulfonyl, arylsulfonyl, C₁-C₁₀ alkylcarbonyl containing 1-6 heteroatoms, C₂-C₂₀ alkylaryl optionally containing 1-6 heteroatoms, or C₂-C₂₀ arylalkyl optionally containing 1-6 heteroatoms; D is H, aryl, heteroaryl, C₁-C₈ alkyl, C₃-C₈ heterocycloalkyl, or —C(O)—R_(d); and each of R_(a), R_(b), R_(b)′, R_(c), R_(c)′, R_(d), and R_(d)′, independently, being H, aryl, or heteroaryl.
 53. The method of claim 52, wherein A is C₁-C₁₂ alkyl, arylsulfonyl, C₁-C₁₀ alkylcarbonyl containing 1-6 heteroatoms, C₂-C₂₀ arylalkyl, or A and B together are heteroaryl.
 54. The method of claim 53, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═; each of R₁ and R₂, independently, is H or C₁-C₈ alkyl; or R₁ and R₂ together are C₅-C₈ cycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₁-C₆ alkoxy, or halogen; and B is H or B and A together are heteroaryl.
 55. The composition of claim 52, wherein D is of formula (II),

wherein each

is a single bond or a double bond; provided that if one

is a double bond, its neighboring

is not a double bond; each of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, independently, is —C═, —CR,—, or —N═; at most two of

X₁′—,

X₂′—,

X₃′—, and

X₄′— being —N═; each of R₁′ and R₂′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, or C₁-C₆ alkylthio; or R₁′ and R₂′ together are C₅-C₈ cycloalkyl or C₅-C₈ heterocycloalkyl; and each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ heterocycloalkyl, OH, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₁-C₆ alkylthio, arylthio, or halogen; or R₄′ and R₅′ together are C₅-C₇ cycloalkyl or C₅-C₇ heterocycloalkyl in which R_(e) is H, aryl, or heteroaryl.
 56. The composition of claim 55, wherein A is C₁-C₁₂ alkyl.
 57. The composition of claim 55, wherein A is C₁-C₁₂ alkyl containing 1-6 heteroatoms and optionally substituted with sulfonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl.
 58. The composition of claim 55, wherein A is C₂-C₂₀ alkylaryl optionally containing 1-6 heteroatoms.
 59. The composition of claim 55, wherein A is aryl, or A and B together are heteroaryl.
 60. The composition of claim 56, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═; each of R₁ and R₂, independently, is H, C₁-C₈ alkyl, or aryl; or R₁ and R₂ together are C₅-C₈ cycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₃-C₈ heterocycloalkyl, OH, C₁-C₆ alkoxy, aryloxy, C₁-C₆ alkylthio, or halogen; B is H or C₁-C₈ alkyl; each of

X₁′—,

X₂′—,

X₃′—, and

X₄—, independently, is —C═; each of R₁′ and R₂′, independently, is H, C₁-C₈ alkyl, or aryl; or R₁′ and R₂′ together are C₅-C₈ cycloalkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, C₃-C₈ heterocycloalkyl, OH, C₁-C₆ alkoxy, aryloxy, C₁-C₆ alkylthio, or halogen.
 61. The composition of claim 57, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═; each of R₁ and R₂, independently, is H or C₁-C₈ alkyl; or R₁ and R₂ together are C₅-C₈ cycloalkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₁-C₆ alkoxy, aryloxy, C₁-C₆ alkylthio, or halogen; B is H; each of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, independently, is —C═; each of R₁′ and R₂′, independently, is H or C₁-C₈ alkyl; or R₁′ and R₂′ together are C₅-C₈ cycloalkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, C₁-C₆ alkoxy, aryloxy, C₁-C₆ alkylthio, or halogen.
 62. The composition of claim 58, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═; each of R₁ and R₂, independently, is H or C₁-C₈ alkyl; each of R₅, R₆, R₇, and R₈, independently, is H, C₁-C₈ alkyl, C₁-C₆ alkoxy, aryloxy, or halogen; B is H; each of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, independently, is —C═; each of R₁′ and R₂′, independently, is H or C₁-C₈ alkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H, C₁-C₈ alkyl, C₁-C₆ alkoxy, aryloxy, or halogen.
 63. The composition of claim 59, wherein each of

X₁—,

X₂—,

X₃—, and

X₄—, independently, is —C═; each of R₁ and R₂, independently, is H or C₁-C₈ alkyl; each of R₅, R₆, R₇, and R₈, independently, is H or C₁-C₈ alkyl; B is H; or B and A together are heteroaryl; each of

X₁′—,

X₂′—,

X₃′—, and

X₄′—, independently, is —C═; each of R₁′ and R₂′, independently, is H or C₁-C₈ alkyl; each of R₃′, R₄′, R₅′, and R₆′, independently, is H or C₁-C₈ alkyl. 